With the promise of curing up to 75% of patients infected with genotype 1 HCV, the approval of the first-generation protease inhibitors (PIs) in May 2011 led to rapid uptake of these then-new agents. Despite the difficult treatment algorithms, less than optimal adverse event (AE) profiles, risk for drug-drug interactions, and the ongoing need for peginterferon, clinicians and patients were motivated by the high SVR rates reported in phase III clinical trials. Unfortunately, the real world proved to be very different from a controlled trial. We all experienced a rude awakening with higher rates of AEs, poorer tolerability, and much lower rates of SVR than we had quoted our patients based on the published data.
With the highly effective new agents now available--and more on the horizon--we need to make sure we do not repeat history.
To achieve excellent results in the real world, we will have to do many things right. The first thing we should probably do is to temper expectations, at least somewhat. The remarkable results reported in phase III trials have appropriately garnered an enormous amount of publicity in the medical and lay press. When more than 95% of patients in multiple trials achieve SVR, it is hard for clinicians and patients not to be incredibly optimistic. However, before assuring our patients that they will almost certainly be cured, we have to make sure that the results apply to them specifically. I remember seeing patients who had anticipated that they had a 75% chance of responding to telaprevir and were disappointed when I pointed out that as a previous null responder with cirrhosis, the likelihood of SVR was closer to 15%. The differences in treatment response rates by baseline characteristics with the new agents are not nearly as stark as with the first-generation PIs. But as an example, the presence of cirrhosis is still quite relevant, affecting the response rates and possibly the duration of therapy. In addition, many of the patients we treat in practice have comorbidities that would have prevented their entry into the highly selected trial populations. Until we have more data on treating specific subpopulations, such as those with renal disease and those older than 65 years of age, we should probably temper our SVR estimates, at least to some degree.
Patients' Experiences Differ and Can Shape Expectations Beyond setting realistic expectations, there are other issues for clinicians to consider in relation to the use of these new agents in the real world. The outstanding results reported in clinical trials may leave us with the sense that treatment is easy and everyone should be treated right away. Treatment is certainly easier, but that is a relative term. For our patients who have struggled through peginterferon and ribavirin for 48 weeks or longer, possibly on more than 1 occasion, these new treatments sound like a cakewalk--and from that perspective, they are. However, for those who have never considered HCV therapy, 3 months of treatment still sounds very daunting. "Interferon free" is only a positive feature if you know the alternative. Getting patients through 8 or 12 weeks of even the best tolerated therapy can still be a challenge, particularly as the patient population expands. To date, we have tackled mostly the low-hanging fruit. Patients had to have been diagnosed, meaning that they had access to some type of healthcare coverage, they had to have been referred to a specialist and to show up to that appointment, the specialist had to deem them acceptable candidates for treatment, and then they had to be willing to take very difficult treatment. The 10% to 15% of the population we have treated up until now is a highly selected, motivated, and relatively comorbidity-free population. Many practitioners have shied away from treating people with active substance use and mental health issues with the easy argument that interferon may complicate these other problems. With the new therapies, this "excuse" is no longer valid, and we will have to deal with the challenges that come along with treating harder-to-access populations. This is not a small point and not a small challenge. Without expanding treatment dramatically, the benefits of the remarkable recent advances in HCV therapy will have little effect at a population level. However, for many hepatologists, treating more marginalized populations will not be easy.
Like everyone else, those with mental health, substance use, and other comorbidities first need to be evaluated to decide whether treatment is the right thing for them. The presence of effective therapy in and of itself is not necessarily an indication for treatment, particularly with treatment that is evolving so quickly. It is still important to first evaluate the stage of liver disease. Fortunately, this is made easier by transient elastography and serum panels, meaning that most patients no longer require a liver biopsy. At the minimum, knowing whether a patient has cirrhosis is critical. Even those cirrhotic patients who achieve SVR will require long-term follow-up to screen for liver cancer. For those without experience of managing advanced liver disease, this is the type of patient who may merit referral. As we have noted, cirrhosis may affect the type and duration of therapy. For example, caution should be used with simeprevir in patients with any signs of decompensation (Child's B or greater) because of unreliable pharmacokinetics. In my clinic, we have seen a few patients with advanced liver disease experience problems while receiving sofosbuvir/simeprevir therapy that needed specialist management. With the coming regimen of ritonavir-boosted paritaprevir plus ombitasvir and dasabuvir, previous null cirrhotics with genotype 1a HCV should probably receive 24 weeks of therapy and will definitely require ribavirin. Similarly, for cirrhotic patients, 8 weeks of sofosbuvir/ledipasvir is not an option, and for those who failed previous treatment, 24 weeks might be of benefit. The improved simplicity of the new regimens can sometimes tempt us to jump to therapy before completing these evaluations.
For patients with minimal or no liver damage and no significant extrahepatic disease, treatment is not an urgent matter. This is not to say we should deny therapy for those patients seeking treatment, but it is important to note that patients with mild disease have time on their side. Hepatitis C disease evolves slowly and treatment options are evolving quickly. Current and near-future 8-week and 12-week regimens will likely be replaced by treatments of just 6 weeks, 4 weeks, or even shorter in the not-too-distant future. Particularly for patients for whom adherence may be a challenge, rushing into therapy can lead to poor outcomes. Even for those with more advanced liver damage, including cirrhosis, treatment is not urgent in terms of weeks or even months. Making sure that patients are able to attend clinic reliably, that they have a good rapport with their treating team, and that important comorbidities and concomitant medications have been reviewed and any issues addressed will ensure much better outcomes on therapy. Even though we will likely have salvage therapies for those who fail initial regimens, it is preferable on all levels to maximize the chance of SVR on the first attempt.
Monitoring Has Multiple Roles to Play One practical challenge that has arisen is how often to see patients. In the absence of rigid stopping rules and with almost every patient achieving undetectable HCV RNA on therapy, there may be a tendency to hand patients a prescription for 3 months of treatment with a follow-up appointment 12 weeks after they finish. However, even for those who cruise through therapy with no problems, follow-up visits are very important. For many patients, knowing that the virus is undetectable, sometimes for the first time after multiple previous treatment attempts, is a huge motivating factor. We have had many patients tell us that our nurses' reminders and encouragement kept them taking their pills when treatment exhaustion set in around Week 8. For stable patients, monthly monitoring is likely adequate, but for those in whom adherence may be an issue, more frequent contact is definitely helpful. In addition, assessing our patients on therapy may bring to light new issues; it was only in clinical practice that anemia was recognized as a problem with telaprevir.
Another practical consideration, which will hopefully soon become less relevant, is treatment access. Coverage for sofosbuvir/simeprevir has been an issue with many payers. The high cost and lack of robust phase III data with this combination have led to denials of coverage for some patients in my clinic. We are hopeful that coverage requests will be more straightforward with the approval of coming regimens; however, the decisions in certain US states to limit therapy for those still using injection drugs must be challenged. Studies have clearly shown that patients who inject drugs can be successfully treated even with interferon-based therapy and the risks of reinfection are surprisingly low. In my opinion, limiting access to therapy based on behaviors is entirely inappropriate and would be akin to refusing to cover statin therapy in patients who smoke or lead sedentary lifestyles. The challenge of access will hopefully be less of an issue because the new regimens will have FDA approval and solid phase III data behind them. However, if access is limited, we as healthcare providers will have a duty to advocate strongly for our patients, particularly for those who do not advocate well for themselves.
The advances in treatment for HCV are nothing short of remarkable. Delivering the successes from clinical trials to the real world is achievable but will take some work. We need to start with realistic expectations and then move forward with therapy for those who need it. Access may be a challenge, but we need to work hard to ensure that everyone who needs therapy gets it. We will need to support patients through treatment, with attention to the stage of liver disease, comorbidities, and treatment adherence. With attention to detail, we can realize the potential of these new therapies, but we have to do it right because we cannot afford--both literally and figuratively--to get it wrong the first time.
A recent article written by a doctor that is well worth the read:
Delivering on the Promise: Maximizing SVR in the Real World
With the promise of curing up to 75% of patients infected with genotype 1 HCV, the approval of the first-generation protease inhibitors (PIs) in May 2011 led to rapid uptake of these then-new agents. Despite the difficult treatment algorithms, less than optimal adverse event (AE) profiles, risk for drug-drug interactions, and the ongoing need for peginterferon, clinicians and patients were motivated by the high SVR rates reported in phase III clinical trials. Unfortunately, the real world proved to be very different from a controlled trial. We all experienced a rude awakening with higher rates of AEs, poorer tolerability, and much lower rates of SVR than we had quoted our patients based on the published data.
With the highly effective new agents now available--and more on the horizon--we need to make sure we do not repeat history.
To achieve excellent results in the real world, we will have to do many things right. The first thing we should probably do is to temper expectations, at least somewhat. The remarkable results reported in phase III trials have appropriately garnered an enormous amount of publicity in the medical and lay press. When more than 95% of patients in multiple trials achieve SVR, it is hard for clinicians and patients not to be incredibly optimistic. However, before assuring our patients that they will almost certainly be cured, we have to make sure that the results apply to them specifically. I remember seeing patients who had anticipated that they had a 75% chance of responding to telaprevir and were disappointed when I pointed out that as a previous null responder with cirrhosis, the likelihood of SVR was closer to 15%. The differences in treatment response rates by baseline characteristics with the new agents are not nearly as stark as with the first-generation PIs. But as an example, the presence of cirrhosis is still quite relevant, affecting the response rates and possibly the duration of therapy. In addition, many of the patients we treat in practice have comorbidities that would have prevented their entry into the highly selected trial populations. Until we have more data on treating specific subpopulations, such as those with renal disease and those older than 65 years of age, we should probably temper our SVR estimates, at least to some degree.
Patients' Experiences Differ and Can Shape Expectations
Beyond setting realistic expectations, there are other issues for clinicians to consider in relation to the use of these new agents in the real world. The outstanding results reported in clinical trials may leave us with the sense that treatment is easy and everyone should be treated right away. Treatment is certainly easier, but that is a relative term. For our patients who have struggled through peginterferon and ribavirin for 48 weeks or longer, possibly on more than 1 occasion, these new treatments sound like a cakewalk--and from that perspective, they are. However, for those who have never considered HCV therapy, 3 months of treatment still sounds very daunting. "Interferon free" is only a positive feature if you know the alternative. Getting patients through 8 or 12 weeks of even the best tolerated therapy can still be a challenge, particularly as the patient population expands. To date, we have tackled mostly the low-hanging fruit. Patients had to have been diagnosed, meaning that they had access to some type of healthcare coverage, they had to have been referred to a specialist and to show up to that appointment, the specialist had to deem them acceptable candidates for treatment, and then they had to be willing to take very difficult treatment. The 10% to 15% of the population we have treated up until now is a highly selected, motivated, and relatively comorbidity-free population. Many practitioners have shied away from treating people with active substance use and mental health issues with the easy argument that interferon may complicate these other problems. With the new therapies, this "excuse" is no longer valid, and we will have to deal with the challenges that come along with treating harder-to-access populations. This is not a small point and not a small challenge. Without expanding treatment dramatically, the benefits of the remarkable recent advances in HCV therapy will have little effect at a population level. However, for many hepatologists, treating more marginalized populations will not be easy.
Like everyone else, those with mental health, substance use, and other comorbidities first need to be evaluated to decide whether treatment is the right thing for them. The presence of effective therapy in and of itself is not necessarily an indication for treatment, particularly with treatment that is evolving so quickly. It is still important to first evaluate the stage of liver disease. Fortunately, this is made easier by transient elastography and serum panels, meaning that most patients no longer require a liver biopsy. At the minimum, knowing whether a patient has cirrhosis is critical. Even those cirrhotic patients who achieve SVR will require long-term follow-up to screen for liver cancer. For those without experience of managing advanced liver disease, this is the type of patient who may merit referral. As we have noted, cirrhosis may affect the type and duration of therapy. For example, caution should be used with simeprevir in patients with any signs of decompensation (Child's B or greater) because of unreliable pharmacokinetics. In my clinic, we have seen a few patients with advanced liver disease experience problems while receiving sofosbuvir/simeprevir therapy that needed specialist management. With the coming regimen of ritonavir-boosted paritaprevir plus ombitasvir and dasabuvir, previous null cirrhotics with genotype 1a HCV should probably receive 24 weeks of therapy and will definitely require ribavirin. Similarly, for cirrhotic patients, 8 weeks of sofosbuvir/ledipasvir is not an option, and for those who failed previous treatment, 24 weeks might be of benefit. The improved simplicity of the new regimens can sometimes tempt us to jump to therapy before completing these evaluations.
For patients with minimal or no liver damage and no significant extrahepatic disease, treatment is not an urgent matter. This is not to say we should deny therapy for those patients seeking treatment, but it is important to note that patients with mild disease have time on their side. Hepatitis C disease evolves slowly and treatment options are evolving quickly. Current and near-future 8-week and 12-week regimens will likely be replaced by treatments of just 6 weeks, 4 weeks, or even shorter in the not-too-distant future. Particularly for patients for whom adherence may be a challenge, rushing into therapy can lead to poor outcomes. Even for those with more advanced liver damage, including cirrhosis, treatment is not urgent in terms of weeks or even months. Making sure that patients are able to attend clinic reliably, that they have a good rapport with their treating team, and that important comorbidities and concomitant medications have been reviewed and any issues addressed will ensure much better outcomes on therapy. Even though we will likely have salvage therapies for those who fail initial regimens, it is preferable on all levels to maximize the chance of SVR on the first attempt.
Monitoring Has Multiple Roles to Play
One practical challenge that has arisen is how often to see patients. In the absence of rigid stopping rules and with almost every patient achieving undetectable HCV RNA on therapy, there may be a tendency to hand patients a prescription for 3 months of treatment with a follow-up appointment 12 weeks after they finish. However, even for those who cruise through therapy with no problems, follow-up visits are very important. For many patients, knowing that the virus is undetectable, sometimes for the first time after multiple previous treatment attempts, is a huge motivating factor. We have had many patients tell us that our nurses' reminders and encouragement kept them taking their pills when treatment exhaustion set in around Week 8. For stable patients, monthly monitoring is likely adequate, but for those in whom adherence may be an issue, more frequent contact is definitely helpful. In addition, assessing our patients on therapy may bring to light new issues; it was only in clinical practice that anemia was recognized as a problem with telaprevir.
Another practical consideration, which will hopefully soon become less relevant, is treatment access. Coverage for sofosbuvir/simeprevir has been an issue with many payers. The high cost and lack of robust phase III data with this combination have led to denials of coverage for some patients in my clinic. We are hopeful that coverage requests will be more straightforward with the approval of coming regimens; however, the decisions in certain US states to limit therapy for those still using injection drugs must be challenged. Studies have clearly shown that patients who inject drugs can be successfully treated even with interferon-based therapy and the risks of reinfection are surprisingly low. In my opinion, limiting access to therapy based on behaviors is entirely inappropriate and would be akin to refusing to cover statin therapy in patients who smoke or lead sedentary lifestyles. The challenge of access will hopefully be less of an issue because the new regimens will have FDA approval and solid phase III data behind them. However, if access is limited, we as healthcare providers will have a duty to advocate strongly for our patients, particularly for those who do not advocate well for themselves.
The advances in treatment for HCV are nothing short of remarkable. Delivering the successes from clinical trials to the real world is achievable but will take some work. We need to start with realistic expectations and then move forward with therapy for those who need it. Access may be a challenge, but we need to work hard to ensure that everyone who needs therapy gets it. We will need to support patients through treatment, with attention to the stage of liver disease, comorbidities, and treatment adherence. With attention to detail, we can realize the potential of these new therapies, but we have to do it right because we cannot afford--both literally and figuratively--to get it wrong the first time.
http://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20Keeping%20Up/Clinical%20Thought/CT%203.aspx